We propose to use the GATA-1low murine model as a tool to define the biologic mechanisms underlying the[unreadable] abnormal hematopoietic stem cell (HSC) and progenitor cell (HPC) trafficking and extramedullary[unreadable] hemopoiesis that characterizes idiopathic myelofibrosis (IM) and identify new targets for the development of[unreadable] drugs to treat this disorder. During this project we will test the hypothesis that HSC/HPC mobilization occurs[unreadable] at specific stages of the disease and that abnormal cell trafficking requires either the generation of a specific[unreadable] cell type (the extramedullary hematopoietic initiating cell, EMH-IC) or mobilization of both HSC/EPC and[unreadable] mesenchymal stem cells (MSC) and/or endothelial progenitor cells (EPC), responsible for generating a[unreadable] permissive hematopoietic microenvironment in a variety of extramedullary sites. To test this hypothesis we[unreadable] will:[unreadable] Specific Aim 1) To characterize the degree of HSC/HPC and MSC/EPC mobilization and trafficking during[unreadable] the course of the development of myelofibrosis in GATA-1low mice.[unreadable] Specific Aim 2) To identify the mechanisms underlying the development of abnormal HSC/HPC trafficking[unreadable] and extramedullary hemopoiesis in GATA-1low mice.[unreadable] Specific Aim 3) To identify treatment strategies for the treatment of each stage of the disease in GATA-1low[unreadable] mice.[unreadable] Relevance: IM is a hematological malignancy associated with abnormal stem cell trafficking and increased[unreadable] extramedullary hematopoiesis. We believe that a side-by-side investigation of the mechanisms leading to[unreadable] abnormal HSC/HPC trafficking and extramedullary hematopoiesis in the mouse model (Project 4) and IM[unreadable] patients (Project 5) will represent a powerful and effective approach to identify the optimal treatment for IM.